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Johannes Wedel, Maria P Stack, Tatsuichiro Seto, Matthew M Sheehan, Kaifeng Liu, Evelyn Flynn, David M Briscoe, The adapter protein TSAd maintains alloimmune T regulatory cell stability and function, The Journal of Immunology, Volume 200, Issue Supplement_1, May 2018, Page 55.8, https://doi.org/10.4049/jimmunol.200.Supp.55.8
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Abstract
TSAd is an SH2 domain containing intracellular adapter molecule that binds to Lck and functions to elicit T cell receptor-mediated signals and cytokine production. Deficient expression has been associated with autoimmunity in humans and mice, but its mechanism of function in Tregs is not known. We used TSAd KO mice to evaluate its function in CD4+ Tregs, and find that KO Tregs suppress effector proliferation in vitro similar to WT Tregs. However, TSAd KO Tregs displayed higher methylation of the TSDR region of the Foxp3 gene suggesting that TSAd may function via epigenetic regulation of Treg stability. TSAd KO Tregs also produced significantly more effector IFNγ upon mitogen stimulation (vs. WT) indicating that they possess proinflammatory function. To assess function in vivo, we transplanted MHC class II mismatched B6.C-H-2bm12 heart transplants into C57BL/6 WT or TSAd KO recipients. While allograft survival was >50 days in WT recipients, allograft rejection was markedly accelerated in TSAd KO recipients (mean survival time [MST] 22 days, P<0.01). By FACS, CD4+CD44hiCD62Llo Teffs expanded in TSAd KO recipients (vs. WT) supporting the possibility that TSAd KO Tregs are less efficient in suppression and/or possess effector function. To further evaluate these possibilities, we adoptively transferred CD4+CD25+ WT or TSAd KO Tregs into C57BL/6 Rag2γc KO recipients of fully MHC mismatched Balb/c allografts on day 2 post-transplant; subsequently WT CD4+CD25− Teffs were transferred on day 18. In this model WT Tregs (MST 68 days) were significantly more efficient than TSAd KO Tregs (MST 48, P<0.05) in suppression of effectors in vivo. Thus, TSAd provides cell-intrinsic signals to suppress proinflammatory effector function in Treg populations.
